Patent GB-1226981-A (GB)
IPC: B01J21/00
Filed: 1968-04-16
Abstract: 1,226,981. Thiophene and furan derivatives. IMPERIAL CHEMICAL INDUSTRIES Ltd. 17 March, 1969 [16 April, 1968; 25 Oct., 1968; 10 Dec., 1968], Nos. 17895/68, 50788/68 and 58666/68 Heading C2C: [Also in Division A5] The invention comprises novel thiophene and furan derivatives of the Formula I wherein X is H, CH 3 , CH 3 CH 2 , Cl or Br, Y is a phenyl radical, optionally substituted by one or two F, Cl, or Br atom(s), and Z is a group of the formula -CR<SP>1</SP>R<SP>2</SP>R<SP>3</SP>, wherein R<SP>1</SP> is H, CH 3  or CH 3 CH 2 , R<SP>2</SP> is H, CH 3  or CH 3 CH 2 , C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl, and R<SP>3</SP> is -CO 2 R<SP>4</SP>, CONHR<SP>5</SP> or CONR<SP>6</SP>, wherein R<SP>4</SP> is H, C 1-5  alkyl, benzyl or phenyl, R<SP>5</SP> is H, OH, NH 2  or C 4-8  dialkylaminoalkyi, and NR<SP>6</SP> is N-piperidino, N-morpholino or N-pyrrolidino, and wherein when R<SP>2</SP> is C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl R<SP>3</SP> is the same radical, and B is O or S, and wherein Y and Z are linked to non- adjacent carbon atoms of the heterocyclic nucleus and when X is H and Y is linked to position 2 of the nucleus, Z is not CH 2 CO 2 R<SP>4</SP> linked to position 5 of the nucleus; and non- toxic pharmaceutically acceptable salts of said compounds, wherein R<SP>3</SP> is a carboxy radical, and non-toxic pharmaceutically acceptable acidaddition salts of said compounds which are sufficiently basic to form said acid-addition salts. The novel compounds are obtained by the following methods: (a) Compounds of the above general formula in which R<SP>2</SP> is H, CH 3  or C 2 H 5  and R<SP>3</SP> is CO 2 R<SP>4</SP>, wherein R<SP>4</SP> is C 1-5  alkyl by reacting the appropriate cyanide with an alkanol of the formula R<SP>4</SP>0H, in the presence of sulphuric or hydrochloric acid, provided that when B is O the acid is hydrochloric acid. (b) Compounds in which both R<SP>1</SP> and R<SP>2</SP> are H and R<SP>3</SP> is CO 2 R<SP>4</SP>, wherein R<SP>4</SP> is H or C 1-5  alkyl by carrying out the Arndt-Eistert reaction on the corresponding halocarbonylthiophene or halocarbonylfuran derivatives. (c) Compounds in which R<SP>2</SP> is H, CH 3  or C 2 H 5  and R<SP>3</SP> is CONH 2  by hydrolysing the appropriate nitriles. (d) Compounds in which R<SP>2</SP> is H, CH 3  or C 2 H 5  and R<SP>3</SP> is CO 2 H by hydrolysing the corresponding compounds in which R<SP>3</SP> is replaced by a radical Cy, where Cy stands for CN, CONH 2 , CSNH 2 , C 2-6  alkoxycarbonyl? C 6 H 5 CH 2 OCO, or C 6 H 5 OCO. (e) Compounds in which R<SP>2</SP> is H, CH 3  or C 2 H 5  and R<SP>3</SP> is CONHR<SP>5</SP> or CONR<SP>6</SP> by reacting the corresponding acid halide with a compound of the formula R<SP>5</SP>NH 2  or HNR<SP>6</SP>. (f) Compounds in which R<SP>2</SP> is H, CH 3  or C 2 H 5  and R<SP>3</SP> is C0 2 R<SP>4</SP>, wherein R<SP>4</SP> is C 1-5  alkyl, benzyl or phenyl, by esterifying the corresponding acids, acid halides or carboxylic acid anhydrides. (g) Compounds in which R<SP>3</SP> is C0 2 R<SP>4</SP> in which R<SP>4</SP> is C 1-5  alkyl, C 6 H 5 CH 2 - or C 6 H 5 - by reacting alkali metal derivatives of the corresponding compounds in which R<SP>1</SP> is H, with methyl or ethyl chloride, bromide or iodide. (h) Compounds in which R<SP>2</SP> and R<SP>3</SP> are both CO 2 R<SP>4</SP>, wherein R<SP>4</SP> is C 1-5  alkyl, C 6 H 5 CH 2  or C 6 H 5 -, by reacting sodium or potassium or a hydride, amide or C 1-4  alkoxide thereof, with carbonates of the formula CO.(OR<SP>4</SP>) 2  and compounds of the above general formula in which R<SP>2</SP> is H or R<SP>3</SP> is CO 2 R<SP>4</SP>. (i) Compounds in which R<SP>2</SP> is H or R<SP>3</SP> is CO 2 H by reacting compound of the above general formula in which both R<SP>2</SP> and R<SP>3</SP> are -CO 2 R4, wherein R<SP>4</SP> is <SP>C</SP>1-5 alkyl, C 6 H 5 CH 2  or C 6 H 5 -, which an inorganic base in the presence of water and under the influence of heat, or, in the case where B is S, with an inorganic acid in the presence of water and under the influence of heat. (j) Compounds in which X is Cl or Br, and R<SP>3</SP> is C0 2 R<SP>4</SP>, wherein R<SP>4</SP> is C 1-5  alkyl, C 6 H 5 CH 2 - or C 6 H 5 - by reacting the corresponding compounds in which X is hydrogen, in the presence of alkali metal acetates, with solutions of chlorine or bromine in organic solvents. (k) Compounds in which R<SP>2</SP> is H, CH 3 , C 2 H 5 , C 4-6  alkoxy carbonyl, C 6 H 5 CH 2 OCO or C 6 H 6 OCO and R<SP>3</SP> is C0 2 R<SP>4</SP>, wherein R<SP>4</SP> is C 3-5  alkyl, C 6 H 5 CH 2  or C 6 H 5 , by reacting corresponding compounds in which R<SP>2</SP> is H, CH 3 , C 2 H 5 , CH 3 OCO or CH 3 CH 2 OCO and R<SP>3</SP> is C0 2 R<SP>4</SP>, wherein R<SP>4</SP> is CH 3  or C 2 H 5 , with a C 3-5  alkanol C 6 H 5 CH 2 OH or C 6 H 5 OH in the presence of dibutyl tin dilaurate at a temperature in the range 25‹ to 200‹ C. (1) Compounds in which R<SP>1</SP> and R<SP>2</SP> are both H and R<SP>3</SP> is CO 2 H by first carrying out the Willgerodt reaction on the corresponding acetyl furan or thiophene derivatives and then hydrolysing the product by means of an inorganic base, and, if desired, converting the resulting salts into the corresponding acids. The following compounds and intermediates are described: Ethyl 5 - p - chlorophenylthien - 2 - ylacetate, 2 - cyanomethyl - 5 - p - chlorophenylthiophene, 2 - chloromethyl - 5 - p - chlorophenylthiophene, 2 - hydroxy - methyl - 5 - p - chlorophenylthiophene, 3 - chlorocarbonyl - 2 - methyl - 5 - phenylthiophene, 3 - carboxy - 2 - methyl - 5 - phenylthiophene, ethyl - 2 - methyl - 5 - phenylthien- 3-yl-carbozylate, 3 - ethoxy - carbonyl - 1 - phenylpentane - 1,4 - dione, 2 - (α - cyanoethyl)-5- p - chlorophenylthiophene, methyl - 5 - p - chlorophenylfur - 2 - ylacetate, sodium 5 - p - chlorophenylthien - 2 - ylacetate, 5 - p - chlorophenylthien - 2 - ylacetic acid hemihydrate, 5 - p - bromophenyl - 3 - chloromethylfuran, 5 - p - bromophenyl - 3 - hydroxymethylfuran, 5 - p - bromophenyl - 3 - ethoxycarbonyl - 2 - methylfuran, and 1 - p - bromophenyl - 3 - ethoxycarbonyl - pentane - 1,4 - dione.